Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology.

Autor: Jiwaji Z; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Tiwari SS; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor's Building, Edinburgh, UK., Avilés-Reyes RX; Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA., Hooley M; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor's Building, Edinburgh, UK., Hampton D; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor's Building, Edinburgh, UK., Torvell M; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor's Building, Edinburgh, UK.; UK Dementia Research Institute at Cardiff University, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., Johnson DA; Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA., McQueen J; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Baxter P; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Sabari-Sankar K; Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA., Qiu J; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., He X; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Fowler J; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Febery J; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Gregory J; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor's Building, Edinburgh, UK., Rose J; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Tulloch J; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Loan J; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Story D; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor's Building, Edinburgh, UK., McDade K; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK., Smith AM; UK Dementia Research Institute at Imperial College, Burlington Danes Building, Hammersmith Hospital, London, W12 0NN, UK., Greer P; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Ball M; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Kind PC; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Matthews PM; UK Dementia Research Institute at Imperial College, Burlington Danes Building, Hammersmith Hospital, London, W12 0NN, UK., Smith C; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor's Building, Edinburgh, UK., Dando O; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Spires-Jones TL; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK., Johnson JA; Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA. jeffrey.johnson@wisc.edu., Chandran S; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK. Siddharthan.Chandran@ed.ac.uk.; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor's Building, Edinburgh, UK. Siddharthan.Chandran@ed.ac.uk., Hardingham GE; UK Dementia Research Institute at the University of Edinburgh, Chancellor's Building, Edinburgh Medical School, Edinburgh, EH16 4SB, UK. Giles.Hardingham@ed.ac.uk.; Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. Giles.Hardingham@ed.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jan 10; Vol. 13 (1), pp. 135. Date of Electronic Publication: 2022 Jan 10.
DOI: 10.1038/s41467-021-27702-w
Abstrakt: Alzheimer's disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPT P301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.
(© 2022. The Author(s).)
Databáze: MEDLINE
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